Mechanism of Estradiol-Induced Block of Voltage-Gated K+ Currents in Rat Medial Preoptic Neurons

Abstract

The present study was conducted to characterize possible rapid effects of 17-β-estradiol on voltage-gated K+ channels in preoptic neurons and, in particular, to identify the mechanisms by which 17-β-estradiol affects the K+ channels. Whole-cell currents from dissociated rat preoptic neurons were studied by perforated-patch recording. 17-β-estradiol rapidly (within seconds) and reversibly reduced the K+ currents, showing an EC50 value of 9.7 µM. The effect was slightly voltage dependent, but independent of external Ca2+, and not sensitive to an estrogen-receptor blocker. Although 17-α-estradiol also significantly reduced the K+ currents, membrane-impermeant forms of estradiol did not reduce the K+ currents and other estrogens, testosterone and cholesterol were considerably less effective. The reduction induced by estradiol was overlapping with that of the KV-2-channel blocker r-stromatoxin-1. The time course of K+ current in 17-β-estradiol, with a time-dependent inhibition and a slight dependence on external K+, suggested an open-channel block mechanism. The properties of block were predicted from a computational model where 17-β-estradiol binds to open K+ channels. It was concluded that 17-β-estradiol rapidly reduces voltage-gated K+ currents in a way consistent with an open-channel block mechanism. This suggests a new mechanism for steroid action on ion channels.

How to Properly Measure a Current-Voltage Relation?—Interpolation vs. Ramp Methods Applied to Studies of GABAA Receptors

“…In many cases, however, the interpolation method likely works well when ion flux is limited, for example by rapid inactivation or desensitization, such as seen in many voltage-gated Na + channels and AMPA receptors, respectively. On the other hand, voltage-gated K + currents in several preparations may contribute significant currents for many seconds or even a minute after an activating voltage step (see e.g., Clay, 1989 ; Druzin et al, 2011 ). Further, large K + currents may cause ion concentration changes not only in the cytosol, but also in the extracellular space between the neuronal membrane and glial cells (Frankenhaeuser and Hodgkin, 1956 ; Moran et al, 1980 ; Clay, 1989 ).…”

Small-Molecule Hormones: Molecular Mechanisms of Action

“…Cell-membrane-located small-molecule hormone receptors interacting with G proteins might also activate adenylate cyclase, which results in the generation of yet another secondary messenger, cAMP, and in the activation of cAMP-dependent proteins, such as PKA, and of their substrates [243–247]. By nongenomic mechanisms, small-molecule hormones also regulate the activity of ion channels, influencing cross-membrane movement of Na + , H + , Cl − , and of K + [245, 248, 249]. …”

Nongenomic modulation of the large conductance voltage- and Ca2+ -activated K+ channels by estrogen: A novel regulatory mechanism in human detrusor smooth muscle

“…Ion channels are particularly important targets for mediating the effects of estrogens. For example, 17b-estradiol has been shown to interact with K + channels, including voltage-gated K + and TASK channels, the latter being a member of the two-pore domain K + channel family (Druzin et al 2011;Hao and Li 2014). Furthermore, 17b-estradiol has been reported to activate the large conductance voltage-and Ca 2+ -activated K + (BK) channels in some smooth muscles including cultured human coronary artery smooth muscle cells (White et al 2002) and colonic myocytes .…”